Chronic pain following surgical incisions is a major clinical problem. As used herein, the term “chronic pain” refers to pain lasting at least three (3) months and typically at least six (6) months, e.g., after surgery, injury or a disease. Currently available therapeutics given for acute post-surgical pain (e.g., opiates and non-steroidal anti-inflammatory drugs, i.e., NSAIDs) do not always prevent the transition to chronic post-surgical pain. Furthermore, opiates and NSAIDs can be habit forming and/or patients develop tolerance to these drugs, thereby requiring increased dosage. Moreover, because these drugs are typically administered orally, many patients suffer adverse gastrointestinal discomfort.
The present invention features AMPK activation as a mechanism for the alleviation of post-surgical, and possibly other persistent pain states and utilization of novel therapeutics that employ this mechanism of action of use in humans. Dysregulated protein translation regulation pathways that underlie persistent pain states can be negatively regulated by activation of endogenous signaling factor AMPK.
As such, the present invention features methods and compositions that use AMPK activators for treating pain, e.g., acute post-surgical pain, transition to chronic pain, etc. (pain may be measured using various parameters including but not limited to acute hypersensitivity and hyperalgesic priming, etc.). The methods and compositions of the present invention may feature a first AMPK activator and a second AMPK activator, wherein the two AMPK activators work synergistically and the AMPK activators are administered in individually sub-efficacious doses. In some embodiments, AMPK activators that have different mechanisms of AMPK activation, such as metformin and resveratrol, are used to accomplish this.